Antihistamine compounds



, salts thereof Patente Aug. l5, i950 2,519,!! ANTII S'IAMINE COMPOUND No Drawing.

Mendham, and Philip J.

toWhite N. 1., a

Application January 4, 1047,

Seth-1N0. 72.31! 1 Chim- (Cl- 260-302) This invention relates to new and novel compounds and to a method for their pre aration, and more particularly to com characterized by havins a high degree 0! antihistamin activity,

It is known that iundamentally, festations of many allergies are due to tissue liberation of histamine brought about by the olfending allergens. In the attempt to relieve such clinical manifestations, it has been proposed administer compounds to the allergic individual which antagonize or pathoiogic eflects of histamine. pounds are referred to as antiehistamine compounds.

Although some progress has been made in this iield there has heretoiore been discovered no compound which is highly eiiective and which is reasonably free from and his toxic eiiects. The advantages could be administered safely and conveniently to an individual suflering from an allergy due to histamine and which could successfully overcome this condition are apparent.

It is therefore an object of the present invention to provide an anti-histamine compound characterized bva low degree of toxicity when used in eiiective amounts.

An additional object is to provide new chemi- 311 compounds useful in treating allergic condions.

An additional object is to provide new compounds usetui as intermediates in the preparation of new and valuable produc An additional object is to provide a method for preparing new and novel amino compounds and having a high degree oi anti-histamine activity.

The compounds 01! the invention include compounds having the general formula clinical mani and salts thereof with acids. In the general formula given X represents a member selected from the group consisting of trivalent nitrogen and the methine radical (-Cl-I==) and R represents a member selected from the group consisting of hydrogen and a radical having the general formula wherein It represents a number selected from of a compound or product which,

the group consisting of dialkylamlno, dicycloallrylamino, N-alkvl-N-cycloalkylamino, i-pyrldino, l-plperidino, i-morpholino and 4-thiamorphoiino radicals, R." represents a member selected from the group consisting of benzyl and nuolearly substituted halo-, and alkyl -benzyl radicals. and n is an integer less than 10. not more than one B representing hydrogen. The aikylene group, -CaH2n-, between the two nitrogen atoms may be straight or branched chain. In a. preieri'ed modification of the invention alkyl and alkoxy radicals substituent on the benzyi radical contain from 1 to 6 carbon atoms inclusive.

Among the compounds of the invention are included:

2 (N(dimethylaminomethyl) N benzyl-amino) -thiazole 2,5 hisilfldimethylarnlnomethyi) N benzylamino) -thiazolc fl-irlmiethyiaminomethyl) -N-benzyl amino)- thiazole 2.5-bis(l-l(diethvlaminomethyl) -N-benzy1 amino) -thiazole 2-(N(dihutylaminomethyl) -N benzyl amino) thiasole 3,5-bir-(N(dibutylaminomethyl)-N-henzy1 amino) -thiazole 2-(N(dicyclohexyiaminomethyl) -N-benzyl amino) -thiazole 2,5-bis(N(dihexylaminomethyl) -N-benzyl amino) -thiazole 2- (N(ethylcyclohexylaminoethyl) -N- benzyl and no) -thiazole 2-(Nimethylethylamlnomethyl) -I-l-benzyl amino) thiazole 2,5-bis(N(methylethylaminomethyl)-i-l benzylamino) -thiazoie 2-(N(bdimethylaminoethy1) -N-benzylamino) thiazoie 2,5-bis(N(b-dimethylaminoethyl) -N-benzyl-amlno) -thiazole 2-(Nib-dimethylaminoethyl) '-N (chlorobenzyl) amino) -thiazole 2,5-bis(Nib-dimethylaminoethyl) -N (ii-chlorobenzyl) -amino) -thiazoie 2- (Nibdimethylaminoethyl) zyl) -amino) -thiazole 2,5-bis(N(b-dimethylaminoethyl) benzyl) -amino) -thiazole 2-(N(b-methylpropylaminoethyl) -N (2 ethylbenzyl) -amino) -thiazoie 2- (N(b-dimethylaminomethyl) -l-l benzyi) -amino) -thiazoie 2,5-bis(N(b-dimethylaminomethyl) -N- (4 onybenzyl) -amino) -thiazole N (4-ethy1- (i-methoxymeth- N (i ethylben- 2-(N(b-diethylaminoethyl)-N-(4-ethoxybenzyl)- are prepared readily by condensing a, z-haloamino) -thiazole thiazole or a 2,5-dlhalothiazole, e. g., z-bromo- 2-fNwlm hylaminolsopropyll-N-benzylamlthiazole or 2,5-dibromothiazole, with a substino) -thiazole tuteu ethylene diamine having the general 2,5-bis(N(b-methylpropylaminoethyl) N (4- 5 formula cthylbenzyl) -amlno) -thiazole R"NH-Ca'Hza-R' m: wherein n. R and R" have the values given previously.

2.54:1:("(b-methylhexylaminoethyl)-N benzylwhen it is desired to prepare a mmpmmd haw mmmm' in: only one substltuent of the character del- (Ntplperidinoethyl) -N- methyl benzyl amino) thluol e 2- (N- (pyrldlnoethyl) -N-benzyl-amlno) thlazole i-(N- (piperidlnornethyl) -N-benzyl-amino) thie w I-(N- ta-morpholinoethyl) N benzyl amino) flliuole (R- (mldino thyll -N-benzyl-amlno) thlazola LtH-(plperidlnomethyl) -N-benzyl-amino) thialole I-(N- fl-morpholinoethyl) N benn-l amino) (NG-thiamorpholino) -N-benzyl-amino) thialole 2541!: (N- (piperldlnomethyl) -N-benzyl amino) thlazole I-(N- (dimethylaminomethyl) N benzyl am!- i -no) -thiophen 2.5411301-(dlethylaminomethyl) N-benzyl amino) -thiophene (N-dieyclohexylaminomethyl) -N-benzyl amino) -thlophene 2.5-bls(N- (methylethylaminomethyl) N benzylamino) -thiophene 2-(N-(b-dimethylaminoethyl) -N- (4 ohlorobenzyll -amino) thiophene 2(N-(b-dlmethylaminoethyl) -N- (4-ethylbenzyl) amino) -thiophene 2- (N- (b-dlmethylamlnoethyl) -N benzyl) -amino) thlophene 2,5-bls( N- (b-dlethylaminomethyl) -N- (4 -ethoxybenzyl) -amino) -thiophene This invention (4 methoxyone basic form salts with one or conditions or pH of A preferred compound is the mono-hydrochloride of 2-(N(b-dimethylamlnoethyl) -N-benzyl-amino) -thiazole, l. e., N.N-dimethyl-N'-benayl-N'- tz-thiazolyl) -ethylenedlamine mono-hydrochloride, described and claimed in a concurrenfly tiled copending application, Serial No, 720.318, now Patent No. 2.440.703, which is espeoially valuable due to its high degree of antitarnine activity, the individual and pre le compounds or the invention having the general formula and prepared by mixture of compounds, find then the tlon. The residue may then be distilled in vacuo fraction collected. The basic compound thus obtained may, if desired, be purlfled, e. g., b

tone. the monohydrochlorlde of pound is obtain may be recrystallized ethyl alcohol and The 'ethylenediamlne derivatives condensed chloride, chloride, z-n-hexylbenzyl bromide. d-methoxybenzyl chlorlde. 2-ethoxybenzyl ride and p-isepropylbeozyl bromide, with an s- N.l-disubstituted alkylene diamine, such as dimcthylaminoethrl amine, diethyiaminomethyl amine. diisopropylaminoethyl amine, b-pyridylethyl amine, -(4-morpholino)-ethyl amine and b(1-piperldino)-ethyl amine. The condensation is carried out by warming the su stances togather. preferably in an inert solvent such as ether, in the presence of a mild alkaline condensing agent, such as sodium or potassium acetate. The reaction product having the formula R"NHCH:-R' may be recovered by evaporating the solvent, taking up the residue in anhydrous alcoholic hydrogen halide, filtering oil undissolved inorganic halide, aikalizlng the illtrate with an aqueous alkali metal hydroxide and extracting the amine from the alkaline mixture with ether. Upon evaporating the other from the extract and fractionally distilling the residue in vacuo, the desired diamine is obtained in substantially pure form. When so prepared the diamino compounds are generally colorless or slightly yellowish, oily liquids practically insoluble in water and soluble in alcohol and ether. They form well defined crystalline salts with one or two chemical equivalents of acids. In

similar manner a benzyl or substituted benzyl amine can be condensed with an N,N-disubstituted alkyl halide to form the desired diamine compound.

An alternate procedure for the preparation of the intermediate compound having the general formula R"NHC,.Ha-R' involves condensing a benzyl or substituted benzyl amine with an alkylene halide, such as dichloromethane, 1,2-dichloroethane, and 1,4-dibromobutane to form an N (gamma-haloalkyl) -benzyl amine which is then condensed with an appropriate amine (diethyl amine, dimethyl amine, piperidine, thiamorphollne and the like) through the gamma halogen atom to introduce the R group, previously defined, into the molecule. Superior yields of products of high purity are obtained by this procedure.

Thiophene compounds of the invention are prepared conveniently in similar manner from bromothiophene or by condensing a 2-amino-or a 2,5-diaminothiophene with a haloamine having the general formula (Hal.=halogen) wherein R has the value given previously. The resulting thiophene derivative is then condensed further with a benzyl halide or substituted benzyl halide, such as those mentioned, to form the desired thiophene compound.

The free thiophene bases form salts similar to those of the thiazole bases.

Certain advantages of the,invention are apparent from the following examples which are given by way at illustration only and are not to be construed as limiting.

Example 1.-N,N-dimethul-N'-benznl-ethylenediamin atlases 8 milliliters being required. The mixture was cooled to room temperature'and precipitated potassium chloride was removed by altering and washing the residue with 75 milliliters of alcohol.

droxide was added and with 800 milliliters of ether. The ethereal extract was dried over solid potassium hydroxide, the

ether evaporated and the oily residue distilled in Example 2.N,N-dimeth1 l-N'Jenni-ethylene diamine One molecular proportion of benzyl amine is refluxed for several hours with one molecular proportion of fused sodium acetate and somewhat more than one molecular proportion of ethylene bromide. The mixture is then stirred into water and sodium carbonate added to a distinct alkalinity. Unreacted ethylene bromide is steam distilled from the mixture and the still residue extracted thoroughly with ether. Upon evaporation of the other there is obtained an oily product consisting principally of N-(b-bromoethynbenzyl-amine. This amine forms a crystalline hydrochloride and picrate.

Equimolecular proportions of dimethyl amine and N-(b-bromoethyl) -benzyl-amine are heated in an autoclave under pressure with about one molecular proportion of sodium acetate. Upon cooling and agitating the contents or the autoclave with dilute sodium hydroxide and then extracting the mixture with ether and evaporating the ether, there is obtained a high yield 0! N,N- dimcthyl-N'-benzyl-ethylenediamine.

Example 3.-2-(N(b-dimethylaminoethyl) -N- bonsai-amino) -thiozole A mixture or 25 grams of z-bromothiazole, 50 grams of N,N-dimethyl-N'-benzyl ethylenedlamine and 35 grams of pyridine was refluxed for 3% hours. The temperature of the liquid during refluxing was about 142 C. The pyridine was then removed by distillation in vacuo until the vapor temperature rose to at 30 millimeters. The residue from the distillation was cooled to room temperature, rendered alkaline by adding 50 milliliters of 20 per cent aqueous sodium hydroxide solution and the mixture, then extracted with 300 milliliters of ether. The ethereal extract was dried over anhydrous sodium carbonate and the ether removed by distillation. The dark, oily residue was then distilled in vacuo and the fraction which boiled at to C. at 15 millimeters was collected separately. This fraction weighed 14.6 grams and consisted principally of 2-(Nib-dimethylaminoethyl) -N-benzyi-amino) -thiazole. The base was purified by conversion to the picrate which, after recrystallization from methanol, melted at 138 to 141 C. The free base was isolated from the picrate by treating the latter with aqueous sodium hydroxide. extracting the mixture with ether and distilling the ether. A solution of 10.1 free base in 10 millimeters of anhydrous alcohol was then mixed with a solution or 1.39 grams oi anhydrous hydrogen chloride in 13.9 milliliters oi anhydrous alcohol. Upon concentrating the rams of the solutlonolavoiumeoizilmillilitersandaddins nohydroehloride oi 2-(N(b-dimethylaminoethyl) -N-benzyll -thianole was pre- Upon niterins the mixture and dryin: the precipitate there was obtained 10.4 grams or the monohydrochioride. Alter recrystallization irom a mixture of 2 parts of ethyl acetate and 1 part 01 anhydrous ethanol and then irom n-butenol, there was obtained 8.4 grams or the purified monohydrochloride in the form of small white flakes melting at 178 to 1'17 C. The monooride was soluble in water, ethanol. and butanol but practically insoluble in ether free iron alcohol trample 4.Z-(N (bdi1nethvlaminoethyll N-beml-amino) -thiophene A mixfiire of 0. mol each of ll-aminothiophene and beta-dimethylaminoethyl chloride and 0.2 moi of pyridine ls refluxed (or about two hours and then mixed with suiiiclent dilute sodium hydroxide to render the mixture strongly alkaline. Pyridine and excess reactants are distilled from the mixture with steam and the still residue cooled and extracted with ether. The ethereal extract is dried over anhydrous sodium suiiate and the ether volatilized. The residue of 2- tN-(h-dimethyiaminoethyl) -amino) -thiophene is heated in alcoholic solution with 0.1 mol of benzyl chloride ior about one hour, then cooled, and mixed with an excess of dilute aqueous sodium hydroxide and distilled with steam to remove unreacted benzyl chloride and alcohol. The still residue is extracted with ether, the ethereal extract dried and the ether vaporized. The oily residue of Z-(N-(b-dimethylaminoethyl) -N-benzyl-amino) -thiophene is converted to the hydrochloride by dissolving it in warm 8 dilute hydrochloric acid and allowins the solutiontoerystaliise. 'l'heyleldisaboutaiipercent or theory based on the z-aminothiophene used.

We claim: A compound selected from the class consisting oi compounds having the general formula ac--x 11-15 B 5 wherein X represents a member selected from the group consisting of trivalent nitrogen and the methine radical and it represents an (N-basicalkylaminol-N-benul-amino radical, and salts theme! with acids.

clAREHCE W. SONDERN. PHILIP J. BREIVOGEL.

REFERENCES CITED The following references are of record in the flle of this patent:

UNITED STATES PATENTS Number Name Date 1,723,695 Hahi et a1. Aug. 6, 1929 1,836,486 Morton Dec. 15, 1931 2,440,703 Bondern et al. May 4, 1948 FOREIGN PATENTS Number Country Date 913,959 France Sept. 1946 OTHER REFERENCES Proceedings of the aociety for Experimental Biology and Medicine, vol. 63, Oct. 1946, page 159.

Chem. Abst, vol. 2'1. page 819, citing German Patent 559,500. 

